Advair hfa

Overdose

No human overdosage data has been reported for %medicine_name%.

%medicine_name% contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to %medicine_name%. Treatment of overdosage consists of discontinuation of %medicine_name% together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

Chronic overdosage of fluticasone propionate may result in signs/symptoms of hypercorticism. Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias.

As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of salmeterol.

Advair HFA price

Contraindications

The use of %medicine_name% is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
• Hypersensitivity to any of the ingredients.

Undesirable effects

Use of LABA may result in the following:

• Serious asthma-related events – hospitalizations, intubations, death
• Cardiovascular and central nervous system effects

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection
• Pneumonia in patients with COPD
• Immunosuppression
• Hypercorticism and adrenal suppression
• Reduction in bone mineral density
• Growth effects
• Glaucoma and cataracts

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The incidence of adverse reactions associated with %medicine_name% in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 3) and 1 active-controlled 12-week U.S. clinical trial (Trial 2). A total of 1,008 adult and adolescent subjects with asthma (556 females and 452 males) previously treated with albuterol alone, salmeterol, or ICS were treated twice daily with 2 inhalations of %medicine_name% 45/21 or %medicine_name% 115/21, fluticasone propionate CFC inhalation aerosol (44-or 110-mcg doses), salmeterol CFC inhalation aerosol 21 mcg, or placebo HFA inhalation aerosol. The average duration of exposure was 71 to 81 days in the active treatment groups compared with 51 days in the placebo group.

Table 2. Adverse Reactions with %medicine_name% with ≥3% Incidence in Adult and Adolescent Subjects with Asthma

The incidence of common adverse reactions reported in Trial 4, a 12-week non-U.S. clinical trial in 509 subjects previously treated with ICS who were treated twice daily with 2 inhalations of %medicine_name% 230/21, fluticasone propionate CFC inhalation aerosol 220 mcg, or 1 inhalation of ADVAIR DISKUS 500/50 was similar to the incidences reported in Table 2.

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that occurred in the groups receiving %medicine_name% with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo include the following: tachycardia, arrhythmias, myocardial infarction, postoperative complications, wounds and lacerations, soft tissue injuries, ear signs and symptoms, rhinorrhea/postnasal drip, epistaxis, nasal congestion/blockage, laryngitis, unspecified oropharyngeal plaques, dryness of nose, weight gain, allergic eye disorders, eye edema and swelling, gastrointestinal discomfort and pain, dental discomfort and pain, candidiasis mouth/throat, hyposalivation, gastrointestinal infections, disorders of hard tissue of teeth, abdominal discomfort and pain, oral abnormalities, arthralgia and articular rheumatism, muscle cramps and spasms, musculoskeletal inflammation, bone and skeletal pain, muscle injuries, sleep disorders, migraines, allergies and allergic reactions, viral infections, bacterial infections, candidiasis unspecified site, congestion, inflammation, bacterial reproductive infections, lower respiratory signs and symptoms, lower respiratory infections, lower respiratory hemorrhage, eczema, dermatitis and dermatosis, urinary infections.

In Trial 3, there were more reports of hyperglycemia among adults and adolescents receiving %medicine_name%, but this was not seen in Trials 1 and 2.

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ADVAIR, fluticasone propionate, and/or salmeterol or a combination of these factors.

Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), hypertension, ventricular tachycardia.

Aphonia, earache, facial and oropharyngeal edema, paranasal sinus pain, rhinitis, throat soreness, tonsillitis.

Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, osteoporosis.

Cataracts, glaucoma.

Dyspepsia, xerostomia.

Abnormal liver function tests.

Immediate and delayed hypersensitivity reactions, including rash and rare events of angioedema, bronchospasm, and anaphylaxis.

Esophageal candidiasis.

Back pain, myositis.

Paresthesia, restlessness.

Fever, pallor.

Agitation, aggression, anxiety, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Asthma; asthma exacerbation; chest congestion; chest tightness; cough; dyspnea; immediate bronchospasm; influenza; paradoxical bronchospasm; tracheitis; wheezing; pneumonia; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Contact dermatitis, contusions, ecchymoses, photodermatitis, pruritus.

Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis.

Therapeutic indications

%medicine_name% is indicated for the twice-daily treatment of asthma in patients aged 12 years and older. %medicine_name% should be used for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta2-adrenergic agonist (LABA).

%medicine_name% is NOT indicated for the relief of acute bronchospasm.

Pharmacodynamic properties

Healthy Subjects:

Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) placebo-controlled crossover trials were conducted with healthy subjects: (1) a cumulative-dose trial using 42 to 336 mcg of salmeterol CFC inhalation aerosol given alone or as %medicine_name% 115/21, (2) a single-dose trial using 4 inhalations of %medicine_name% 230/21, salmeterol CFC inhalation aerosol 21 mcg, or fluticasone propionate CFC inhalation aerosol 220 mcg, (3) a single-dose trial using 8 inhalations of %medicine_name% 45/21, %medicine_name% 115/21, or %medicine_name% 230/21, and (4) a single-dose trial using 4 inhalations of %medicine_name% 230/21; 2 inhalations of ADVAIR DISKUS 500/50; 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg; or 1,010 mcg of fluticasone propionate given intravenously. In these trials pulse rate, blood pressure, QTc interval, glucose, and/or potassium were measured. Comparable or lower effects were observed for %medicine_name% compared with ADVAIR DISKUS or salmeterol alone. The effect of salmeterol on pulse rate and potassium was not altered by the presence of different amounts of fluticasone propionate in %medicine_name%.

Hypothalamic-Pituitary-Adrenal Axis Effects: The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in 3 of these trials. Compared with fluticasone propionate CFC inhalation aerosol, %medicine_name% had less effect on 24-hour urinary cortisol excretion and less or comparable effect on 24-hour serum cortisol. In these crossover trials in healthy subjects, %medicine_name% and ADVAIR DISKUS had similar effects on urinary and serum cortisol.

Subjects with Asthma:

Cardiovascular Effects: In clinical trials with %medicine_name% in adult and adolescent subjects aged 12 years and older with asthma, systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) were similar to or slightly lower in patients treated with %medicine_name% compared with patients treated with salmeterol CFC inhalation aerosol 21 mcg. In 61 adult and adolescent subjects with asthma given %medicine_name% (45/21 or 115/21 mcg), continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of twice-daily therapy, and no clinically significant dysrhythmias were noted.

The effect of 21 days of treatment with %medicine_name% 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. There were no notable changes from baseline for QTc, heart rate, or systolic and diastolic blood pressure.

Hypothalamic-Pituitary-Adrenal Axis Effects: A 4-way crossover trial in 13 subjects with asthma compared pharmacodynamics at steady state following 4 weeks of twice-daily treatment with 2 inhalations of %medicine_name% 115/21, 1 inhalation of ADVAIR DISKUS 250/50 mcg, 2 inhalations of fluticasone propionate HFA inhalation aerosol 110 mcg, and placebo. No significant differences in serum cortisol AUC were observed between active treatments and placebo. Mean 12-hour serum cortisol AUC ratios comparing active treatment with placebo ranged from 0.9 to 1.2. No statistically or clinically significant increases in heart rate or QTc interval were observed for any active treatment compared with placebo.

In a 12-week trial in adult and adolescent subjects with asthma, %medicine_name% 115/21 was compared with the individual components, fluticasone propionate CFC inhalation aerosol 110 mcg and salmeterol CFC inhalation aerosol 21 mcg, and placebo. All treatments were administered as 2 inhalations twice daily. After 12 weeks of treatment with these therapeutic doses, the geometric mean ratio of urinary cortisol excretion compared with baseline was 0.9 for %medicine_name% and fluticasone propionate and 1.0 for placebo and salmeterol. In addition, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation in 23 to 32 subjects per treatment group, remained intact for the majority of subjects and was similar across treatments. Three (3) subjects who received %medicine_name% 115/21 had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing, compared with 1 subject who received placebo, 2 subjects who received fluticasone propionate 110 mcg, and 1 subject who received salmeterol.

In another 12-week trial in adult and adolescent subjects with asthma, %medicine_name% 230/21 (2 inhalations twice daily) was compared with ADVAIR DISKUS 500/50 (1 inhalation twice daily) and fluticasone propionate CFC inhalation aerosol 220 mcg (2 inhalations twice daily). The geometric mean ratio of 24-hour urinary cortisol excretion at week 12 compared with baseline was 0.9 for all 3 treatment groups.

The effect of 21 days of treatment with %medicine_name% 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) on serum cortisol was evaluated in 31 children aged 4 to 11 years with mild asthma. There were reductions in serum cortisol from baseline in all treatment groups (14%, 22%, and 13% for %medicine_name%, %medicine_name% with spacer, and ADVAIR DISKUS, respectively).

Subjects with Asthma:

Hypothalamic-Pituitary-Adrenal Axis Effects: In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 mcg/dL assessed by radioimmunoassay) were noted both in subjects receiving fluticasone propionate and in subjects receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year trial carried out with the DISKHALER inhalation device in 64 subjects with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no subject receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol <18 mcg/dL). With a peak cortisol threshold of <35 mcg/dL, 1 subject receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another subject receiving fluticasone propionate (5%) had an abnormal response at 2 years. No subject on placebo had an abnormal response at 1 or 2 years.

Subjects with Asthma:

Cardiovascular Effects: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). In 2 double-blind asthma trials, subjects receiving either 42 mcg of salmeterol inhalation aerosol twice daily (n = 81) or 180 mcg of albuterol inhalation aerosol 4 times daily (n = 80) underwent continuous electrocardiographic monitoring during four 24-hour periods; no clinically significant dysrhythmias were noted.

Short-acting Beta2-agonists:

In three 12-week U.S. clinical trials, the mean daily need for additional beta2-agonist use in 277 subjects receiving %medicine_name% was approximately 1.2 inhalations/day and ranged from 0 to 9 inhalations/day. Two percent (2%) of subjects receiving %medicine_name% in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular adverse events was observed among subjects who averaged 6 or more inhalations per day.

Methylxanthines:

The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by subjects receiving %medicine_name% has not been completely evaluated. In five 12-week clinical trials (3 U.S. and 2 non-U.S.), 45 subjects receiving %medicine_name% 45/21, %medicine_name% 115/21, or %medicine_name% 230/21 twice daily concurrently with a theophylline product had adverse event rates similar to those in 577 subjects receiving %medicine_name% without theophylline.

Fluticasone Propionate Nasal Spray:

In subjects receiving %medicine_name% in three 12-week U.S. clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between subjects receiving FLONASE (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 89) and those who were not (n = 192).

Pharmacokinetic properties

Fluticasone Propionate:

Healthy Subjects: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed.

Three (3) single-dose, placebo-controlled, crossover trials were conducted in healthy subjects: (1) a trial using 4 inhalations of %medicine_name% 230/21, salmeterol CFC inhalation aerosol 21 mcg, or fluticasone propionate CFC inhalation aerosol 220 mcg, (2) a trial using 8 inhalations of %medicine_name% 45/21, %medicine_name% 115/21, or %medicine_name% 230/21, and (3) a trial using 4 inhalations of %medicine_name% 230/21; 2 inhalations of ADVAIR DISKUS 500/50; 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg; or 1,010 mcg of fluticasone propionate given intravenously. Peak plasma concentrations of fluticasone propionate were achieved in 0.33 to 1.5 hours and those of salmeterol were achieved in 5 to 10 minutes.

Peak plasma concentrations of fluticasone propionate (N = 20 subjects) following 8 inhalations of %medicine_name% 45/21, %medicine_name% 115/21, and %medicine_name% 230/21 averaged 41, 108, and 173 pg/mL, respectively.

Systemic exposure (N = 20 subjects) from 4 inhalations of %medicine_name% 230/21 was 53% of the value from the individual inhaler for fluticasone propionate CFC inhalation aerosol and 42% of the value from the individual inhaler for salmeterol CFC inhalation aerosol. Peak plasma concentrations from %medicine_name% for fluticasone propionate (86 versus 120 pg/mL) and salmeterol (170 versus 510 pg/mL) were significantly lower compared with individual inhalers.

In 15 healthy subjects, systemic exposure to fluticasone propionate from 4 inhalations of %medicine_name% 230/21 (920/84 mcg) and 2 inhalations of ADVAIR DISKUS 500/50 (1,000/100 mcg) was similar between the 2 inhalers (i.e., 799 versus 832 pg•h/mL, respectively), but approximately half the systemic exposure from 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg (880 mcg, AUC = 1,543 pg•h/mL). Similar results were observed for peak fluticasone propionate plasma concentrations (186 and 182 pg/mL from %medicine_name% and ADVAIR DISKUS, respectively, and 307 pg/mL from the fluticasone propionate CFC inhalation aerosol). Absolute bioavailability of fluticasone propionate was 5.3% and 5.5% following administration of %medicine_name% and ADVAIR DISKUS, respectively.

Subjects with Asthma:

A double-blind crossover trial was conducted in 13 adult subjects with asthma to evaluate the steady-state pharmacokinetics of fluticasone propionate and salmeterol following administration of 2 inhalations of %medicine_name% 115/21 twice daily or 1 inhalation of ADVAIR DISKUS 250/50 twice daily for 4 weeks. Systemic exposure (AUC) to fluticasone propionate was similar for %medicine_name% (274 pg•h/mL [95% CI: 150, 502]) and ADVAIR DISKUS (338 pg•h/mL [95% CI: 197, 581]).

The effect of 21 days of treatment with %medicine_name% 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in a trial of 31 children aged 4 to 11 years with mild asthma. Systemic exposure to fluticasone propionate was similar with ADVAIR DISKUS and %medicine_name% with a spacer (138 pg•h/mL [95% CI: 69, 273] and 107 pg•h/mL [95% CI: 46, 252], respectively) and lower with %medicine_name% without a spacer (24 pg•h/mL [95% CI: 10, 60]).

Salmeterol Xinafoate:

Healthy Subjects: Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect.

Peak plasma concentrations of salmeterol (N = 20 subjects) following 8 inhalations of %medicine_name% 45/21, %medicine_name% 115/21, and %medicine_name% 230/21 ranged from 220 to 470 pg/mL.

In 15 healthy subjects receiving %medicine_name% 230/21 (920/84 mcg) and ADVAIR DISKUS 500/50 (1,000/100 mcg), systemic exposure to salmeterol was higher (317 versus 169 pg•h/mL) and peak salmeterol concentrations were lower (196 versus 223 pg/mL) following %medicine_name% compared with ADVAIR DISKUS, although pharmacodynamic results were comparable.

Subjects with Asthma:

Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended dosages (42 mcg of salmeterol inhalation aerosol twice daily). Following chronic administration of an inhaled dose of 42 mcg of salmeterol inhalation aerosol twice daily, salmeterol was detected in plasma within 5 to 10 minutes in 6 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 150 pg/mL at 20 minutes and no accumulation with repeated doses.

A double-blind crossover trial was conducted in 13 adult subjects with asthma to evaluate the steady-state pharmacokinetics of fluticasone propionate and salmeterol following administration of 2 inhalations of %medicine_name% 115/21 twice daily or 1 inhalation of ADVAIR DISKUS 250/50 twice daily for 4 weeks. Systemic exposure to salmeterol was similar for %medicine_name% (53 pg•h/mL [95% CI: 17, 164]) and ADVAIR DISKUS (70 pg•h/mL [95% CI: 19, 254]).

The effect of 21 days of treatment with %medicine_name% 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol was similar for %medicine_name%, %medicine_name% with spacer, and ADVAIR DISKUS (126 pg•h/mL [95% CI: 70, 225], 103 pg•h/mL [95% CI: 54, 200], and 110 pg•h/mL [95% CI: 55, 219], respectively).

Fluticasone Propionate:

Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Salmeterol:

The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

Fluticasone Propionate:

The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for <0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Salmeterol:

Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces.

An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α-hydroxysalmeterol in vitro.

Fluticasone Propionate:

Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Terminal half-life estimates of fluticasone propionate for %medicine_name%, ADVAIR DISKUS, and fluticasone propionate CFC inhalation aerosol were similar and averaged 5.6 hours.

Salmeterol:

In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only).

The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days. No terminal half-life estimates were calculated for salmeterol following administration of %medicine_name%.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

Pregnancy Category C. There are no adequate and well-controlled trials with %medicine_name% in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, %medicine_name% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking %medicine_name%.

Fluticasone Propionate and Salmeterol:

In the mouse reproduction assay, fluticasone propionate at a dose approximately equivalent to the maximum recommended human daily inhalation dose (MRHDID) (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg) combined with salmeterol at a dose approximately 580 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg) produced cleft palate, fetal death, increased implantation loss, and delayed ossification. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 1/5 the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 80 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1.4 mg/kg).

In rats, combining fluticasone propionate at a dose equivalent to the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg) and a dose of salmeterol at approximately 1,200 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg) produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were seen when combining fluticasone propionate at a dose less than the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg) and a dose of salmeterol at approximately 120 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1 mg/kg).

Fluticasone Propionate:

Mice and rats at fluticasone propionate doses less than or equivalent to the MRHDID (on a mcg/m2 basis at maternal subcutaneous doses of 45 and 100 mcg/kg, respectively) showed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses approximately equivalent to the MRHDID (on a mcg/m2 basis at maternal inhaled doses up to 68.7 mcg/kg).

In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose less than the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 4 mcg/kg). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 6 times the MRHDID (on a mcg/m2 basis at maternal oral doses up to 300 mcg/kg). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

Salmeterol:

No teratogenic effects occurred in rats at salmeterol doses approximately 230 times the MRHDID (on a mg/m2 basis at maternal oral doses up to 2 mg/kg). In pregnant Dutch rabbits administered salmeterol doses approximately 25 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/kg and higher), salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at a salmeterol dose approximately 10 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/kg).

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 2,300 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg). Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Qualitative and quantitative composition

Inhalation aerosol: Purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister containing 60 or 120 metered inhalations and fitted with a counter. Each actuation delivers a combination of fluticasone propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) from the mouthpiece.

%medicine_name% 45/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0715-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0715-22).

%medicine_name% 115/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0716-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0716-22).

%medicine_name% 230/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0717-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0717-22).

Each canister is fitted with a counter and supplied with a purple actuator with a light purple strapcap. Each inhaler is sealed in a plastic-coated, moisture-protective foil pouch with a desiccant that should be discarded when the pouch is opened. Each inhaler is packaged with a Medication Guide leaflet.

The purple actuator supplied with %medicine_name% should not be used with any other product canisters, and actuators from other products should not be used with an %medicine_name% canister.

The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000.

Keep out of reach of children. Avoid spraying in eyes.

Contents under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator.

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C). Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use. SHAKE WELL FOR 5 SECONDS BEFORE EACH SPRAY.

Manufactured by: GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: Dec 2017

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonists).

Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, 1 trial compared mometasone furoate/formoterol with mometasone furoate, and 1 trial compared budesonide/formoterol with budesonide. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related.

The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older

The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27).

A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.

%medicine_name% should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. %medicine_name% has not been studied in subjects with acutely deteriorating asthma. The initiation of %medicine_name% in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of %medicine_name%, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of %medicine_name% with a higher strength, adding additional ICS, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily of %medicine_name%.

%medicine_name% should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. %medicine_name% has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with %medicine_name%, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

%medicine_name% should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using %medicine_name% should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with %medicine_name%. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with %medicine_name% continues, but at times therapy with %medicine_name% may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

Lower respiratory tract infections, including pneumonia, have been reported in patients with chronic obstructive pulmonary disease (COPD) following the inhaled administration of corticosteroids, including fluticasone propionate and ADVAIR DISKUS. In 2 replicate 1-year trials in 1,579 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the subjects treated with ADVAIR DISKUS was higher in subjects older than 65 years (9%) compared with the incidence in subjects younger than 65 years (4%).

In a 3-year trial in 6,184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% with ADVAIR DISKUS 500/50, 14% with fluticasone propionate 500 mcg, 11% with salmeterol 50 mcg, and 9% with placebo). Similar to what was seen in the 1-year trials with ADVAIR DISKUS 250/50, the incidence of pneumonia was higher in subjects older than 65 years (18% with ADVAIR DISKUS 500/50 versus 10% with placebo) compared with subjects younger than 65 years (14% with ADVAIR DISKUS 500/50 versus 8% with placebo).

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although %medicine_name% may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to %medicine_name%. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with %medicine_name%. Lung function (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to %medicine_name% may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

Fluticasone propionate, a component of %medicine_name%, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of %medicine_name% in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing %medicine_name%.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with %medicine_name% should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, %medicine_name% should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with %medicine_name% is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.

As with other inhaled medicines, %medicine_name% can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with %medicine_name%, it should be treated immediately with an inhaled, short-acting bronchodilator; %medicine_name% should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving %medicine_name%.

Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of %medicine_name%.

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Therefore, %medicine_name%, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Salmeterol, a component of %medicine_name%, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to longterm consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving %medicine_name% routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including %medicine_name%, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of ICS, including fluticasone propionate, a component of %medicine_name%. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

In rare cases, patients on inhaled fluticasone propionate, a component of %medicine_name%, may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other ICS in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established.

%medicine_name%, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Large doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with %medicine_name% at recommended doses.

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with %medicine_name%, there is not a significant increase in the risk of these events.

Inform patients that %medicine_name% is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following:

• Decreasing effectiveness of inhaled, short-acting beta2-agonists
• Need for more inhalations than usual of inhaled, short-acting beta2-agonists
• Significant decrease in lung function as outlined by the physician

Tell patients they should not stop therapy with %medicine_name% without physician/provider guidance since symptoms may recur after discontinuation.

Instruct patients not to use other LABA for asthma.

Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with %medicine_name%, but at times therapy with %medicine_name% may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia.

Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Advise patients that %medicine_name% may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to %medicine_name%.

Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of %medicine_name%. Patients should discontinue %medicine_name% if such reactions occur.

Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.

Inform patients that orally inhaled corticosteroids, including fluticasone propionate, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Inform patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 5 times the MRHDID on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the MRHDID on a mg/m2 basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test.

No evidence of impairment of fertility was observed in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHDID on a mg/m2 basis). Prostate weight was significantly reduced.

In an 18-month carcnogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 10 times the MRHDID based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 2 times the MRHDID for adults based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 80 times the MRHDID on a mg/m2 basis). No tumors were seen at 0.21 mg/kg (approximately 25 times the MRHDID on a mg/m2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 230 times the MRHDID on a mg/m2 basis).

Pregnancy Category C. There are no adequate and well-controlled trials with %medicine_name% in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, %medicine_name% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking %medicine_name%.

Fluticasone Propionate and Salmeterol:

In the mouse reproduction assay, fluticasone propionate at a dose approximately equivalent to the maximum recommended human daily inhalation dose (MRHDID) (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg) combined with salmeterol at a dose approximately 580 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg) produced cleft palate, fetal death, increased implantation loss, and delayed ossification. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 1/5 the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 80 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1.4 mg/kg).

In rats, combining fluticasone propionate at a dose equivalent to the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg) and a dose of salmeterol at approximately 1,200 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg) produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were seen when combining fluticasone propionate at a dose less than the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg) and a dose of salmeterol at approximately 120 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1 mg/kg).

Fluticasone Propionate:

Mice and rats at fluticasone propionate doses less than or equivalent to the MRHDID (on a mcg/m2 basis at maternal subcutaneous doses of 45 and 100 mcg/kg, respectively) showed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses approximately equivalent to the MRHDID (on a mcg/m2 basis at maternal inhaled doses up to 68.7 mcg/kg).

In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose less than the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 4 mcg/kg). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 6 times the MRHDID (on a mcg/m2 basis at maternal oral doses up to 300 mcg/kg). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.

Fluticasone propionate crossed the placenta following subcutaneous administration

Dosage (Posology) and method of administration

%medicine_name% should be administered as 2 inhalations twice daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

More frequent administration or a greater number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of %medicine_name% is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using %medicine_name% should not use additional LABA for any reason.

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.

For patients aged 12 years and older, the dosage is 2 inhalations twice daily, approximately 12 hours apart.

When choosing the starting dosage strength of %medicine_name%, consider the patients’ disease severity, based on their previous asthma therapy, including the ICS dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation.

The maximum recommended dosage is 2 inhalations of %medicine_name% 230/21 twice daily.

Improvement in asthma control following inhaled administration of %medicine_name% can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of %medicine_name% with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of %medicine_name% with a higher strength, adding additional ICS, initiating oral corticosteroids) should be considered.

Prime %medicine_name% before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray.

Interaction with other medicinal products and other forms of interaction

Use of LABA may result in the following:

• Serious asthma-related events – hospitalizations, intubations, death
• Cardiovascular and central nervous system effects

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection
• Pneumonia in patients with COPD
• Immunosuppression
• Hypercorticism and adrenal suppression
• Reduction in bone mineral density
• Growth effects
• Glaucoma and cataracts

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The incidence of adverse reactions associated with %medicine_name% in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 3) and 1 active-controlled 12-week U.S. clinical trial (Trial 2). A total of 1,008 adult and adolescent subjects with asthma (556 females and 452 males) previously treated with albuterol alone, salmeterol, or ICS were treated twice daily with 2 inhalations of %medicine_name% 45/21 or %medicine_name% 115/21, fluticasone propionate CFC inhalation aerosol (44-or 110-mcg doses), salmeterol CFC inhalation aerosol 21 mcg, or placebo HFA inhalation aerosol. The average duration of exposure was 71 to 81 days in the active treatment groups compared with 51 days in the placebo group.

Table 2. Adverse Reactions with %medicine_name% with ≥3% Incidence in Adult and Adolescent Subjects with Asthma

The incidence of common adverse reactions reported in Trial 4, a 12-week non-U.S. clinical trial in 509 subjects previously treated with ICS who were treated twice daily with 2 inhalations of %medicine_name% 230/21, fluticasone propionate CFC inhalation aerosol 220 mcg, or 1 inhalation of ADVAIR DISKUS 500/50 was similar to the incidences reported in Table 2.

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that occurred in the groups receiving %medicine_name% with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo include the following: tachycardia, arrhythmias, myocardial infarction, postoperative complications, wounds and lacerations, soft tissue injuries, ear signs and symptoms, rhinorrhea/postnasal drip, epistaxis, nasal congestion/blockage, laryngitis, unspecified oropharyngeal plaques, dryness of nose, weight gain, allergic eye disorders, eye edema and swelling, gastrointestinal discomfort and pain, dental discomfort and pain, candidiasis mouth/throat, hyposalivation, gastrointestinal infections, disorders of hard tissue of teeth, abdominal discomfort and pain, oral abnormalities, arthralgia and articular rheumatism, muscle cramps and spasms, musculoskeletal inflammation, bone and skeletal pain, muscle injuries, sleep disorders, migraines, allergies and allergic reactions, viral infections, bacterial infections, candidiasis unspecified site, congestion, inflammation, bacterial reproductive infections, lower respiratory signs and symptoms, lower respiratory infections, lower respiratory hemorrhage, eczema, dermatitis and dermatosis, urinary infections.

In Trial 3, there were more reports of hyperglycemia among adults and adolescents receiving %medicine_name%, but this was not seen in Trials 1 and 2.

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ADVAIR, fluticasone propionate, and/or salmeterol or a combination of these factors.

Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), hypertension, ventricular tachycardia.

Aphonia, earache, facial and oropharyngeal edema, paranasal sinus pain, rhinitis, throat soreness, tonsillitis.

Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, osteoporosis.

Cataracts, glaucoma.

Dyspepsia, xerostomia.

Abnormal liver function tests.

Immediate and delayed hypersensitivity reactions, including rash and rare events of angioedema, bronchospasm, and anaphylaxis.

Esophageal candidiasis.

Back pain, myositis.

Paresthesia, restlessness.

Fever, pallor.

Agitation, aggression, anxiety, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Asthma; asthma exacerbation; chest congestion; chest tightness; cough; dyspnea; immediate bronchospasm; influenza; paradoxical bronchospasm; tracheitis; wheezing; pneumonia; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Contact dermatitis, contusions, ecchymoses, photodermatitis, pruritus.

Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis.

%medicine_name% has been used concomitantly with other drugs, including short-acting beta2-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma without adverse drug reactions. No formal drug interaction trials have been performed with %medicine_name%.

Fluticasone propionate and salmeterol, the individual components of %medicine_name%, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with %medicine_name% is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.

Fluticasone Propionate:

A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Fluticasone Propionate:

Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

Salmeterol:

In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

%medicine_name% should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of %medicine_name%, on the vascular system may be potentiated by these agents.

Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of %medicine_name%, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

The ECG changes and/or hypokalemia that may result from the administration of non–potassiumsparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as salmeterol, a component of %medicine_name%, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of %medicine_name% with non–potassium-sparing diuretics.